Neurological disorders are disorders that affect the central nervous system, the peripheral nervous system or the autonomic nervous system.
There has recently been some evidence presented in the literature that tau protein is not only implicated in neurodegenerative disorders such as Alzheimer's disease, but also in other neurological disorders, [Satch et al., 2006; Wen et al., 2004; Roberson et al., 2007; Deutsch et al., 2006; Bartosik-Psujek, 2006, Ost et al., 2006].
One type of abnormal tau protein is hyperphosphorylated tau protein. Tau protein is known to be phosphorylated at a number of phosphorylation sites by glycogen synthase kinase 3β (GSK3β) in vivo, including the Alzheimer's disease specific Ser396 residue [Li and Paudel, 2006]. In turn, GSK3β is known to be phosphorylated by the protein kinase Akt and the activity of Akt is known to be attenuated by the protein phosphatase PP2A.
It has recently been shown that PP2A accounts for approximately 71% of the total tau phosphatase activity of human brain [Liu et al., 2005]. The total phosphatase activity and the activities of PP2A toward tau are significantly decreased in brains of Alzheimer's disease patients whereas that of other phosphatases such as PP2B are actually increased in the Alzheimer's disease brain [Liu et al., 2005]. PP2A activity negatively correlates to the level of tau phosphorylation at most phosphorylation sites in human brains. This indicates that PP2A is the major tau phosphatase that regulates its phosphorylation at multiple sites in human brain. This implies that the abnormal hyperphosphorylation of tau is partially due to a downregulation of PP2A activity in the Alzheimer's disease brain and that agents that can act to boost the activity of PP2A would have clinical utility in treating and/or preventing development of some neurological disorders.
There is a need for agents that reduce the amount of tau protein or affect the phosphorylation of tau protein and are clinically useful in the treatment or prevention of neurological disorders.